Variable Phenotypes of ZC4H2-Associated Rare Disease in Six Patients

Abstract

PurposeWieacker-Wolff syndrome is a rare disease caused by X-linked zinc finger C4H2-type containing (ZC4H2) mutations. It is characterized by arthrogryposis multiplex congenita (AMC) and intellectual disability (ID), including impairment of central and peripheral synaptic plasticity. Currently, it is named “ZC4H2-associated rare disease” (ZARD) due to various clinical features other than AMC and ID. Here, we report six cases of ZARD, and describe their variable clinical phenotypes.MethodsWe analyzed the detailed clinical features and genotypes of six patients diagnosed by whole-exome sequencing or a chromosomal microarray.ResultsIn the four male patients, hemizygous mutations were found (c. 245A>C in two patients, c. 610C>A in one patient, and c.637C>T in one patient), and all variants were identified by Sanger sequencing. In the female patients, a 1.16-Mb deletion in Xq11.2, including ZC4H2, was identified by chromosomal microarray. All patients had heterogeneous phenotypes with variable severities. Motor delay was observed in all patients, four of whom could not walk independently. Other neurological features included ID, spasticity, and seizures. The craniofacial features included microcephaly, low-set ears, strabismus, ptosis, ocular motor apraxia, a U-shaped upper lip vermilion, short neck, and microretrognathia. The most common musculoskeletal symptoms were multiple arthrogryposis: metacarpophalangeal joint contracture, clubfoot, distal muscle weakness, Achilles tendon contracture, knee flexion contracture, camptodactyly, elbow flexion contracture, and hip subluxation.ConclusionThe ZARD phenotypes were prominent in male patients, and female patients with loss of function showed more severe symptoms. Further research is needed to clarify phenotypic variability in this rare disorder.